The present invention is directed generally to medical solutions, containers for storing medical solutions and oxygen indicators for detecting the presence of oxygen in a medical container More particularly, the present invention is directed to ready-to-use ternary parenteral nutritional formulations for certain patient populations, particularly fluid limited populations, the container systems for long-term storage and selective administration of such formulations and oxygen indicators for such container systems. More specifically, the present invention is directed to such formulations being stored in flexible containers having multiple chambers for isolated long-term storage of the various nutritional components of such formulations, oxygen indicators for alerting healthcare professionals of an oxygen compromised container and containers facilitating selective sterile admixing into a ready to infuse formulation and administration of such formulation. Even more specifically, the invention is directed to multi-chamber containers allowing selective admixing of two or more solutions contained in the chambers such as nutritional solutions of lipids, carbohydrates, amino acids and electrolytes and oxygen indicators able to withstand heat sterilization and having acceptable storage characteristics.
Medical solutions such as parenteral and enteral nutrient solutions, dialysis solutions, pharmacological solutions, and chemotherapy solutions are routinely stored in a variety of containers made of glass or plastic. While glass containers offer many benefits such as gas impermeability and virtually complete compatibility with medical solutions, glass containers are heavy, easily broken, difficult to handle and can release aluminum into the solutions. As a result, more and more medical solutions are being stored in plastic containers Flexible containers such as bags made from plastic films have gained increased acceptance.
Frequently the prescription to be administered to a patient is comprised of components which are not compatible for long storage periods. One method of overcoming this limitation is to combine or compound the components just prior to administration. Such compounding may be accomplished manually or with automated compounders. However such a combination method is time consuming, may give rise to errors in formulation and increases the risks of contamination of the final mixture.
To overcome the drawbacks of long term incompatibility and reduce the risks of compounding, flexible containers can be formed with multiple chambers for separately storing medical solutions. These bags are formed with frangible connections or peal seals which provide for mixing of the all the contents of the chambers by manipulation of the connections or seals. A drawback of utilizing such multi-chamber containers is that one is restricted to the formulation which are provided by the supplied components and proportional amounts which are housed in the various chambers. When seeking to address the needs of varying patient populations, particularly fluid restricted populations, such restriction may hinder the ability to utilize such a containers, cause use of only a portion of the contents of such a container or cause multiple versions of such containers to be stored.
As described previously, flexible containers having multiple chambers such as multi-chamber bags have separation means that permit communication and mixing of the separately stored components or solutions. Some such multiple chamber containers utilize frangible valves while others use a score line or line of weakness in the barrier separating the chambers to effect mixing of the separately stored components. Still others use tear strips or tear tabs. More advantageous multi-chamber containers in terms of cost and ease of use are of the type which include peel seals formed by heat or radio frequency sealing of the two sheets of thermoplastic material that comprise a flexible bag to define multiple interior chambers. The heat seal provides a barrier that is resistant to unintentional opening forces but is openable with the application of a specific force. These types of multiple chamber containers are disclosed in U.S. Pat. No. 6,319,243 which is incorporated herein by reference.
Plastic containers such as those just discussed however can also present unique issues which must be addressed. One possible issue is that heat sterilization such as autoclaving can affect certain plastic materials used to form the container and/or the heat seal separating the chambers. Another possible issue is that certain plastic materials are permeable to atmospheric oxygen and may inadequately protect oxygen sensitive solutions or components. Yet another is that certain fat soluble or lipophilic solutions or components may not be compatible with certain plastic materials. For example, lipid formulations such as Lipid emulsions used in parenteral nourishment cannot be stored in certain plastics because it can leach out some plastic material from the container, The lipid emulsion would be contaminated and the plastic containers integrity can be compromised.
Lipid emulsions are generally one component of a parenteral nutritional solution (PN). Ternary parenteral nutritional formulations are used to provide all the nutritional components required by a patient. These PN formulations include also a carbohydrate component, an amino acid component, vitamin, trace element and electrolytes components. Because of various incompatibilities, nutritional components of PN formulations are prime examples of medical solutions that cannot be stored long term as a mixture in a ready-to-use state. They can only be combined in a relatively short time period prior to administration.
The individual constituents of each component should be determined by the nutritional recommended requirements of the particular patient population to be treated. For example, PN formulations for adult patients may have different constituents in each component or at least different amounts of each constituent than PN formulations for infants. Moreover, preparation of the separate components of PN formulations for premature infants, neonatal patients or small children presents unique problems. For one, the volume of fluid that may be infused into such patients is relatively small. Seeking to provide all of the desired nutritional components in such a low volume is extremely difficult. For example, the concentration ranges for individual constituents of certain component solutions must be narrowly constricted In addition, some of the individual constituents are either interdependent or incompatible if present in certain forms and concentrations. For example, the breadth of the acceptable concentration range for magnesium for a premature infant is about 0.2 mmol. In other words, the difference between the lowest acceptable concentration of magnesium and the highest acceptable concentration of magnesium is 0.2 mmol. In addition, there is a limit to the amount of chloride a premature infant can tolerate; so in an attempt to provide the required amount of certain electrolytes such as magnesium and calcium as a chloride, the chloride maximum may be exceeded. Furthermore, electrolytes such as calcium and phosphate may be incompatible in certain concentration levels.
Also, storing the components of a PN formulation in a single or multi-chamber plastic container for sterile mixing to form the PN formulation also presents unique problems. As already discussed above, the lipid component is incompatible with certain plastic material In addition, some of the components are sensitive to oxygen which can permeate through certain plastics. Overwraps or overpouches are typically used to restrict the ability of oxygen to get to the multi-chamber containers; however, the overwrap may still allow a small amount of oxygen to diffuse through. In addition, the overwrap may develop a leak which would allow an excessive amount of oxygen to be exposed to the container. Such a leak may not be visible and the presence of such oxygen needs to be indicated to the health care provider, While oxygen indicators exist they appear to not be able to withstand heat sterilization and still function properly after prolonged storage. In other words, the oxygen indicator should be able to indicate the presence of oxygen (oxidized form or positive result) such as with a change in color that is distinguishable from the condition indicating a lack of presence oxygen (reduced form or negative result). Additionally, the oxidized and reduced colors of the indicator should not fade or alter after prolonged storage so as to create uncertainty as to the result.
Furthermore, certain amino acids with thiol function, such as cysteine or acetyl-cysteine can form hydrogen sulfide as a decomposition product during sterilization. An excessive level of hydrogen sulfide may negatively affect some of the nutritional components. Moreover, while the all the separately stored components are mixed to form the final PN formulation prior to administration, there are circumstances when it is undesirable to include one or more of the components found in one of the chambers in the final solution. For example, it may be desirable to not include the lipid component in the final solution for infants under septic status, coagulation abnormalities, high bilirubin level or for other reasons.
Therefore, there is a need for a flexible multiple chamber container that facilitates selective opening of one but not another frangible barrier, less than all the frangible barriers or the frangible barriers in a sequential manner.
There is also a need for individual components of a PN formulation that meets the recommended volume and nutritional requirements for certain patient populations and in particular infants or small children at different stages of development.
In addition, there is a need for means of providing a reliable indicator that atmospheric oxygen may have contaminated the contents of the container, a low level of hydrogen sulfide in case the formulation contains cysteine or derivatives amino acids and an oxygen absorber to eliminate residual oxygen in the overpouch. It would be desirable to provide absorbers and/or indicators that can withstand heat sterilization and prolonged storage and still possess the ability to indicate that an unacceptable amount of oxygen has been exposed to the container.